ClinVar Genomic variation as it relates to human health
NM_000535.7(PMS2):c.1552G>A (p.Glu518Lys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(8); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000535.7(PMS2):c.1552G>A (p.Glu518Lys)
Variation ID: 219612 Accession: VCV000219612.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p22.1 7: 5987213 (GRCh38) [ NCBI UCSC ] 7: 6026844 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 19, 2017 May 1, 2024 Dec 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000535.7:c.1552G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000526.2:p.Glu518Lys missense NM_001322003.2:c.1147G>A NP_001308932.1:p.Glu383Lys missense NM_001322004.2:c.1147G>A NP_001308933.1:p.Glu383Lys missense NM_001322005.2:c.1147G>A NP_001308934.1:p.Glu383Lys missense NM_001322006.2:c.1396G>A NP_001308935.1:p.Glu466Lys missense NM_001322007.2:c.1234G>A NP_001308936.1:p.Glu412Lys missense NM_001322008.2:c.1234G>A NP_001308937.1:p.Glu412Lys missense NM_001322009.2:c.1147G>A NP_001308938.1:p.Glu383Lys missense NM_001322010.2:c.991G>A NP_001308939.1:p.Glu331Lys missense NM_001322011.2:c.619G>A NP_001308940.1:p.Glu207Lys missense NM_001322012.2:c.619G>A NP_001308941.1:p.Glu207Lys missense NM_001322013.2:c.979G>A NP_001308942.1:p.Glu327Lys missense NM_001322014.2:c.1552G>A NP_001308943.1:p.Glu518Lys missense NM_001322015.2:c.1243G>A NP_001308944.1:p.Glu415Lys missense NR_136154.1:n.1639G>A non-coding transcript variant NC_000007.14:g.5987213C>T NC_000007.13:g.6026844C>T NG_008466.1:g.26894G>A LRG_161:g.26894G>A LRG_161t1:c.1552G>A - Protein change
- E518K, E207K, E415K, E331K, E383K, E412K, E327K, E466K
- Other names
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- Canonical SPDI
- NC_000007.14:5987212:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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PMS2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
5163 | 5257 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (1) |
criteria provided, single submitter
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Dec 23, 2023 | RCV000206422.11 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 29, 2023 | RCV000213296.12 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Sep 14, 2023 | RCV000587309.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000765957.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 12, 2018 | RCV001160656.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 30, 2023 | RCV003997572.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Jul 25, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697301.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The PMS2 c.1552G>A (p.Glu518Lys) variant involves the alteration of a non-conserved nucleotide and is present outside of the known functional domains. 4/4 in … (more)
Variant summary: The PMS2 c.1552G>A (p.Glu518Lys) variant involves the alteration of a non-conserved nucleotide and is present outside of the known functional domains. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 2/120582 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). This variant was observed in one patient with early onset colorectal cancer who had a family history of colorectal cancer and her tumor showed stable microsatellite (Chubb 2015). Multiple clinical diagnostic laboratories have classified this variant as uncertain significance. Because of the absence of sufficient clinical information and the lack of functional studies, the variant is currently classified as a variant of uncertain significance (VUS) until additional information becomes available. (less)
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Uncertain significance
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Mismatch repair cancer syndrome 1
Lynch syndrome 4
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000897378.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(Jan 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 4
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001322471.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Uncertain significance
(Mar 22, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001134581.3
First in ClinVar: Jan 05, 2020 Last updated: Jan 01, 2022 |
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Uncertain significance
(Sep 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000279141.11
First in ClinVar: May 29, 2016 Last updated: Sep 22, 2023 |
Comment:
Observed in individuals with colon cancer (Chubb et al., 2015; Haraldsdottir et al., 2017); In silico analysis supports that this missense variant does not alter … (more)
Observed in individuals with colon cancer (Chubb et al., 2015; Haraldsdottir et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25559809, 28466842) (less)
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Uncertain significance
(Jan 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000903147.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glutamic acid with lysine at codon 518 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein … (more)
This missense variant replaces glutamic acid with lysine at codon 518 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 25559809, 28466842). A case-control study did not produce conclusive evidence for the association of this variant with colorectal cancer (PMID: 28466842). This variant has been identified in 5/251300 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Dec 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000259586.10
First in ClinVar: Feb 02, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 518 of the PMS2 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 518 of the PMS2 protein (p.Glu518Lys). This variant is present in population databases (rs376142390, gnomAD 0.004%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 25559809, 28466842). ClinVar contains an entry for this variant (Variation ID: 219612). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PMS2 protein function with a negative predictive value of 80%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Likely benign
(Jun 18, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000273555.7
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain Significance
(Nov 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004844185.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces glutamic acid with lysine at codon 518 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein … (more)
This missense variant replaces glutamic acid with lysine at codon 518 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 25559809, 28466842). A case-control study did not produce conclusive evidence for the association of this variant with colorectal cancer (PMID: 28466842). This variant has been identified in 5/251300 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 7
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2. | Haraldsdottir S | Nature communications | 2017 | PMID: 28466842 |
Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing. | Chubb D | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2015 | PMID: 25559809 |
IUPred: web server for the prediction of intrinsically unstructured regions of proteins based on estimated energy content. | Dosztányi Z | Bioinformatics (Oxford, England) | 2005 | PMID: 15955779 |
Text-mined citations for rs376142390 ...
HelpRecord last updated Jun 10, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.